Sucralose, 4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose, a sweetener with a sweetness intensity several hundred times that of sucrose, is derived from sucrose by replacing the hydroxyl groups in the 4, 1′, and 6′ positions with chlorine. Synthesis of sucralose is technically challenging because of the need to selectively replace specific hydroxyl groups with chlorine atoms, while preserving other hydroxyl groups including a highly reactive primary hydroxyl group. Numerous approaches to this synthesis have been developed. See, e.g., U.S. Pat. Nos. 4,362,869; 4,826,962; 4,980,463; and 5,141,860, which are expressly incorporated by reference herein. However, such approaches typically provide a product that contains varying levels of other chlorinated sugar compounds in addition to sucralose. Although much effort has been directed toward the synthesis of sucralose, the isolation of sucralose in highly pure form from this complex mixture of contaminants heretofore has received relatively little attention. Early reported work typically involved crystallizing sucralose directly from the synthesis mixture, a process that yields a material with high impurity levels. Sucralose is sometimes purified from a synthesis mixture by silica gel chromatography. See, e.g., U.S. Pat. No. 5,128,248, which is expressly incorporated by reference herein. That procedure, due to its use of silica gel, may be ill-suited to large-volume commercial production of highly pure sucralose. In addition, relatively little attention has been focused on other approaches for removing halogenated sugar impurities from sucralose. Efficient removal of these impurities is important because, even at quite low concentrations, they can have an adverse impact on the sweetness, taste, and flavor-modifying properties of sucralose.
One particular problem that decreases the yield and purity of sucralose is the reluctance of sucralose to crystallize under conditions that would result in rapid crystallization of non-substituted sugars in a relatively pure crystal form. In comparison to sucrose solutions, saturated solutions of sucralose crystallize relatively slowly despite the introduction of seed crystals, and the presence of the various di-, tri-, and tetrachlorosucrose derivatives further interferes with the formation of pure sucralose crystals.
A second problem associated with sucralose purification is the relatively large amount of sucralose that remains in the solution after sucralose crystallization, which reduces overall yield. This solution, known in the art as the “mother liquor” or “recrop,” contains one or more undesirable impurities. A simple mathematical analysis illustrates the poor yield obtained by purification based on iterative crystallizations when recovery of material from the mother liquors is not employed. For example, if 60% of the material in each crystallization step is recovered as crystals, the overall yield of four iterative crystallizations would be 0.6×0.6×0.6×0.6, or less than 13%.
Another problem associated with purity and yield of sucralose relates to the formation of a wide range of related chlorinated carbohydrates during sucralose synthesis, which are only partially removed during purification. These related compounds, or impurities, have varying degrees of sweetness, and can interact with the flavor systems of food and beverage products in adverse ways. Various compendial sources, such as the Food and Drug Codex, the United States Pharmacopoeia, and Joint Expert Committee on Food Additives have established specifications for sucralose. All of these authorities allow impurities in sucralose of up to 2%. Individuals can detect sweetness differences arising from impurities when the impurity level is as low as about 1%, and even lower impurity levels can affect the perceived taste of complex flavor systems. Hence, chlorinated carbohydrates created during sucralose synthesis may have a profound effect on taste, affecting the quality of an end product. Conversely, the removal of impurities may beneficially affect taste, sweetness, and palatability.
Pure sucralose can be made by purifying the blocked or partially blocked sucralose precursors, deblocking the precursors, and then isolating sucralose. Another approach is to deblock the pure sucralose and then purify and isolate the sucralose. Another approach is to partially purify the blocked or partially blocked sucralose precursors, deblock the precursors, and then purify and isolate the sucralose. Therefore, the purification of these precursor compounds is needed to increase the overall yield of subsequent reaction steps.
Sucralose and the blocked or partially blocked sucralose precursors can be purified by crystallization, liquid-liquid extraction, or chromatography. Recrystallization, re-extraction, and further chromatography can be used to enhance purity. Unlike sucrose and most carbohydrates, however, the crystallization of sucralose and the blocked or partially blocked sucralose precursors from crude solutions containing other chlorinated carbohydrates and blocked or partially blocked chlorinated carbohydrates produces crystals that contain significant amounts of these other compounds. This is in marked contrast to the crystallization of sucrose, which results in relatively pure crystals. In all cases the recovery of sucralose and blocked or partially blocked sucralose precursors in the crystallization process is less than 100%, and more typically about 50%, resulting in significant loss of sucralose during purification.
Various methods have been developed related to sucralose extraction. For example, U.S. Pat. No. 4,343,934, expressly incorporated by reference herein, relates to the crystallization of sucralose from an aqueous solution, followed by two cycles of heating the remaining mother liquor, concentrating, adding seed crystals, and cooling. The three cycles of crystallization provided an overall yield of 76.6%. U.S. Pat. No. 4,362,869, expressly incorporated by reference herein, shows 4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose penta-acetate (TOSPA) as a precursor of sucralose in one synthetic route but does not identify impurities or recycle mother liquors.
U.S. Pat. No. 4,380,476, expressly incorporated by reference herein, relates to a process in which TOSPA is purified by three sequential crystallizations, followed by deacylation to yield sucralose, and then a single crystallization of sucralose from the product stream. No pre-crystallization extraction is used, and no recycling of the mother liquor is employed. This process purportedly achieves a purity of 99%; however, the yield of this process is quite low (5%).
U.S. Pat. No. 4,405,654 relates to synthetic routes for synthesizing various halosucrose derivatives and is expressly incorporated by reference herein. The compounds are isolated by ion exchange chromatography or by crystallization from solvents such as diethyl ether, ethyl acetate, and petrol.
U.S. Pat. No. 4,980,463, expressly incorporated by reference herein, relates to various processes for purifying sucralose-6-benzoate, a precursor to sucralose in some synthetic routes, including crystallization followed by recrystallization. Also shown is an extractive crystallization, which combines extraction and a first crystallization in a single step. U.S. Pat. No. 5,298,611, expressly incorporated by reference herein, relates to an extractive purification process during crystallization of the sucralose pentaester. In this procedure, the sucralose pentaester is present in an impure reaction mixture in a solvent such as toluene. Water is added to create a biphasic mixture, which is cooled to induce the crystallization of the sucralose pentaester. The pentaester form is then purified, and sucralose in relatively pure form is recovered by hydrolysis of the ester. The water provides a second phase into which the polar materials are extracted, leading to production of purer sucralose pentaester crystals.
U.S. Pat. No. 5,498,709, expressly incorporated by reference herein, relates to a process in which a crude sucralose reaction mixture is extracted with ethyl acetate in a ROBATEL counter current extractor. The ethyl acetate solution of sucralose is then concentrated to a syrup, dissolved in water, treated with a decolorizing agent, again concentrated to a syrup, and diluted in ethyl acetate. The solution is seeded with sucralose crystals, and crystallization is allowed to proceed for several days.
U.S. Pat. No. 5,530,106, also expressly incorporated by reference herein, relates to a process in which sucralose-6-acetate in a reaction mixture is extracted with ethyl acetate (using either batch extraction or a counter current extraction processes) and then crystallized after being combined with the mother liquor from the second crystallization of a previous batch and the second crop solid from the previous batch. In a second crystallization step, once crystallized sucralose-6-acetate is combined with the mother liquor from the third crystallization of a previous batch and crystallized from a mixture of water and ethyl acetate. A third crystallization is performed by dissolving the twice-crystallized material in a mixture of water and ethyl acetate. This thrice-crystallized material is then deacetylated and purified to yield sucralose.
The preceding discussion identifies an unmet need for a sucralose purification process that produces sucralose compositions of enhanced purity and also minimizes the overall loss of sucralose during the purification process.